Field of the Invention
The present invention relates to the field of optical imaging and therapeutics. More particularly, embodiments of the present invention provide minimally-invasive Fiberoptic Microneedle Devices (FMDs) for light-based therapeutics, which physically penetrate tissue and deliver light directly into the target area below the skin surface (FIG. 1). Embodiments of the invention enable depth-selective and deep photothermal therapeutics and include methods of treating cancer, methods of re-shaping or removing adipose tissue, and methods of delivering drugs or co-delivering drugs and energy to selected tissue.
Description of the Related Art
A major limitation for bio-imaging, including optical imaging and therapeutics (such as hair removal or optical tomography techniques, such as OCT imaging), is the shallow penetration depth of light in turbid tissue such as skin. Due to both scattering and absorption of the laser's photons by inhomogeneous tissue structures within the epidermis and dermis such as cells, collagen fibers, and aqueous ground substance, it is difficult if not impossible to maintain a focused or collimated beam past 1 mm depth into tissue. In particular, due to photon scattering around water-encapsulated and water-containing cells, focused light penetration into subcutaneous tissue is prevented, rendering the maximum typical photonic penetration depth of only a few millimeters. Enhancing photonic delivery past this current barrier would enable more selective, deeper, light-based therapeutics and diagnostics.
Currently, light-based therapeutics including oncology treatments, dermatology treatments, cosmetic surgeries, and alternative medicine protocols are limited in the results achieved and/or are not desirable by patients due to the pain typically associated with current procedures for performing these treatments. More specifically, applications that could benefit from improved light-based therapeutics (in particular, increased light penetration in skin) include a broad range of therapeutics ranging from the treatment of deep skin cancers, central nervous system cancers such as malignant gliomas (MGs), bladder cancers such as urothelial cell carcinomas (UCCs) to cosmetic procedures such as laser hair removal, especially for darker-skinned patients and targeted fat removal. By reaching targets beneath the skin surface, such as blood vessels, hair follicles, subdermal fat, and tattoo particles, to name a few, laser-based therapies and cosmetic applications including skin tightening, wrinkle removal, body contouring (fat reshaping or removal), and cellulite reduction could be substantially improved.
For example, minimally invasive laser-based hyperthermia therapy of cancers under the skin, such as melanoma, is currently not feasible due to the shallow penetration of light past the tumor surface. Such therapeutics could be feasible, however, by delivering light several millimeters deep in the tumor. By directly delivering optical radiation in near proximity to target tissue by way of minimally invasive optical fiber needles, the optical dose can be more precise, reducing unwanted collateral tissue damage and associated pain, and faster wound healing (with less scarring and bleeding) can be achieved. Increasing the amount of light penetration could also lead to the detection (and treatment) of tumors located several millimeters beneath the skin's surface through the use of laser-based methods.
Previous research has demonstrated that the light penetration problem can be overcome by using optical fibers to mechanically penetrate skin tissue for the purposes of transmitting light into desired areas. See Prudhomme, M., et al., 1996, “Interstitial Diode Laser Hyperthermia in the Treatment of Subcutaneous Tumor,” Lasers in Surgery and Medicine, 19(4), pp. 445-450, the disclosure of which is incorporated by reference herein in its entirety.
Additionally, it has been known to place a silica optical fiber inside a 3.05 mm thick metal cannula with a light diffusing cap made from quartz. Robinson, D. S., et al., 1998, “Interstitial Laser Hyperthermia Model Development for Minimally Invasive Therapy of Breast Carcinoma,” Journal of the American College of Surgeons, 186(3), pp. 284-292, the disclosure of which is incorporated by reference herein in its entirety. This design was used to deliver 1064 nm Nd:YAG laser light several centimeters deep into breast tumors.
Vertical cavity surface emitting lasers (VCSELs) are also known. For example, U.S. Pat. No. 7,027,478, entitled “Microneedle Array Systems,” the disclosure of which is incorporated by reference herein in its entirety, discloses a device comprising an array of hollow microneedles that are 250 microns in length and have an entrance hole that is 175-200 microns in diameter and an exit hole diameter of 125 microns. Within the hollow portion of the needle (the interior channel) an optical fiber is placed for transmission of light through the needle (which is made of metal and is prepared using photolithography or laser drilling, or is made of high-temperature plastic). Such needles are large and could cause unnecessary damage if inserted into skin. Further, the disclosure does not support extending the technology to smaller needles, and is silent on using additional support means for supporting and guiding the needles during insertion into skin, due to the needles themselves being made of a material (metal or plastic) and having a configuration (large) the combination of which provides sufficient strength to the needles themselves.
Other probe designs were developed for use in diagnostic methods such as optical coherence tomography and optical spectroscopy. See Li, X. D., et al., 2000, “Imaging Needle for Optical Coherence Tomography,” Optics Letters, 25(20), pp. 1520-1522; and Utzinger, U., and Richards-Kortum, R. R., 2003, “Fiber Optic Probes for Biomedical Optical Spectroscopy,” Journal of Biomedical Optics, 8(1), pp. 121-147, the disclosures of both of which are incorporated by reference herein in their entireties. The fiberoptic probes used in these studies, however, are on the order of 300 μm to several millimeters in diameter. See, e.g., Robinson 1998; Prudhomme 1996; Li 2000; and Mumtaz, H., et al. 1996, “Laser Therapy for Breast Cancer Mr Imaging and Histopathologic Correlation,” Radiology, 200(3), pp. 651-658, the disclosure of which is incorporated by reference herein in its entirety.
With respect to physically penetrating skin (e.g., by mechanical means), while reducing or eliminating pain typically encountered by patients undergoing these procedures, it would be desirable to follow a pain-free microneedle model provided in nature—the mosquito fascicle. A mosquito has evolved to penetrate the skin with a flexible biological needle that is extremely small and flexible, inserting it into the skin to draw a meal of blood. The subsequent irritation caused by a mosquito bite is due to the allergic reaction to the saliva that the mosquito secretes during the blood draw to prevent platelet aggregation, not due to the needle insertion itself. See, Ribeiro, J. M. C. and I. M. B. Francischetti, “Role of arthropod saliva in blood feeding: Sialome and post-sialome perspectives,” Annual Review of Entomology, 2003, 48: pp. 73-88, the disclosure of which is incorporated by reference herein in its entirety.
Mosquito-performed blood extraction is done through the fascicle which is covered by an outer sheath called the labium. An SEM photograph of a fascicle tip protruding from the end of the partially retracted labium is shown in FIG. 2. See, Ramasubramanian, M. K., et al., “Mechanics of a mosquito bite with applications to microneedle design,” Bioinspiration & Biomimetics, 2008, 3(4), the disclosure of which is incorporated by reference herein in its entirety. The dimensions of the mosquito fascicle are typically 1.8 mm long with a 40 μm outer diameter. The tip of the fascicle is very sharp, tapering from about 10 μm to less than 1 μm over the last 50 μm of the fascicle. The fascicle is a polymeric microneedle composed of a ductile material, chitin, with an elastic modulus between 10 and 200 GPa (Ramasubramanian 2008) (similar to the inventive silica microneedles). The critical buckling load for a typical fascicle alone is very low (˜3 mN) and not sufficient to penetrate the skin (>10 mN required); however, the lateral support provided by the labium increases the critical buckling load by a factor of 5 and permits successful skin penetration.
Buckling is the most common mode of failure for slender objects forced along their axial direction. This is true for silica-fiber-based fiberoptic microneedles as well. Increasing the buckling force of light guiding needles having a length/diameter ratio of approximately 50 is a challenge. The critical buckling force of a straight cylindrical column with fixed ends can be approximated using Euler's equation. See, Wang, C. M., Wang C. Y., Reddy, J. N., “Exact Solutions for Buckling of Structural Members,” CRC Series in Computational Mechanics and Applied Analysis, 2004, the disclosure of which is incorporated by reference herein in its entirety.
A microneedle 2 mm long can safely penetrate skin if its diameter is larger than about 150 μm, which is close to the size of a wood splinter or a standard optical fiber, which are both known to penetrate the skin and inflict some level of pain. As shown in FIG. 3, the critical buckling force of silica microneedles (E=73 GPa for silica) with 2 mm unsupported length is plotted vs. diameter, and, for comparison, the penetration force required for microneedle insertion into skin obtained from results by Davis et al. is also shown. See, Davis, S. P., et al., “Insertion of microneedles into skin: measurement and prediction of insertion force and needle fracture force,” Journal of Biomechanics, 2004, 37(8): p. 1155-1163, the disclosure of which is incorporated by reference herein in its entirety.
In order to improve the feasibility of using much smaller, less invasive nano- and micro-needles in clinical applications, the critical buckling force of the needles must be improved. Enhancing photonic transmission depth without absorption and scattering to allow imaging and light-based therapeutics below the epidermis (top 100 μm) and dermis (1-2 mm thick below epidermis) would have important implications in basic research (individual cell imaging), tissue engineering, and tissue therapeutics.
What is needed, and what embodiments of the present invention provide, are thinner fiberoptic microneedles (140 μm or less in diameter) for substantially reducing the morbidity and associated pain caused by insertion of needles into living tissue.
In addition, malignant tumors of the central nervous system are the third leading cause of cancer-related deaths in adolescents and adults and the leading cause of death in children with a mean survival time of 15 months and a mortality rate exceeding 95%. In the past few decades, there has been a steady increase in the incidence of brain cancers and, given the aging population, brain tumors will soon be one of the most commonly encountered human neoplasms. Common approaches to the treatment of aggressive brain tumors such as MGs involve surgery, radiation therapy, and/or various chemotherapeutic regimens and combinations of these three modalities. Previous studies have shown that neither single nor multimodality treatments are curative with the combination of adjunctive therapies using radiation and the chemotherapeutic drug, temozolomide, improving survival by only a few months to a rate of 26%. See, Stupp, R., et al., “Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.” N Engl J Med, 2005. 352(10): p. 987-96, the disclosure of which is incorporated by reference herein in its entirety. These statistics have not changed significantly in 70 years, despite intense medical research focused on improving treatment. At present, treatment of both primary and secondary brain tumors is provided to improve or sustain neurological function of the patient, to diminish the size of the tumor growing intracranially, and to lengthen intervals between treatments. One of the reasons for poor survival is that glioma cells typically infiltrate up to 2 cm beyond the volume of visible tumor, making them difficult to detect and treat. These distant, infiltrating cells may be a key factor in tumor progression and resistance to therapy. Treatment of MGs is also limited by insufficient delivery of chemotherapy drugs due to the blood-brain-barrier.
Current treatments include, but are not limited to, convection-enhanced delivery (CED), which has emerged as a promising method for the delivery of high concentrations of macromolecules to larger regions of brain tissue. The principle of CED involves the stereotactically-guided insertion of a small-caliber catheter into the brain. Through this catheter, infusate is pumped into the brain parenchyma and is pushed primarily through the interstitial space. Infusion is continued for up to several days. In contrast to the millimeter distances obtained with simple diffusion, CED has been shown in laboratory experiments to deliver high-molecular-weight proteins 2 cm into the brain parenchyma after 2 hours of continuous infusion. See Vandergrift, W. A., et al., “Convection-enhanced delivery of immunotoxins and radioisotopes for treatment of malignant gliomas.” Neurosurg Focus, 2006. 20(4): p. E13, the disclosure of which is incorporated by reference herein in its entirety. This was accomplished without causing cerebral edema and was unaffected by capillary loss or metabolism of the macromolecule. Compared with other therapies, CED is advantageous by exposing regional brain tissue to high concentrations of chemotherapeutic agents while minimizing systemic and CNS toxicity. However, although CED has achieved greater efficacy than traditional systemic chemotherapy, it has yielded only minor improvements in survival for Phase III clinical trials. This can be attributed to the limited ability of CED to 1) uniformly distribute drug throughout the tumor and 2) broadly disseminate drug to the infiltrative MG cells residing in the primary tumor periphery (not detected by MRI) which correlate with tumor recurrence. The anatomical heterogeneity of the brain is a major limiting factor in perfusion by CED. Portions of the brain are inherently difficult to saturate with drugs due to variations in permeability of white and gray matter, tumor tissue, cerebrospinal fluid tracts, and anatomy of vascular beds. The high lipid content of the brain makes predictable movement of aqueous drug formulations problematic. Also, traditional catheters do not possess the arborizing capability to effectively perfuse drug target to distant infiltrative cells. See Raghavan, R., et al., “Convection-enhanced delivery of therapeutics for brain disease, and its optimization.” Neurosurg Focus, 2006. 20(4): p. E12, the disclosure of which is incorporated by reference herein in its entirety. CED efficacy is also limited by the inability to accurately position the catheter and dynamically monitor and control drug distribution.
Clinical and laboratory evidence has shown that hyperthermia (elevated temperature) enhances the cytotoxic effects of several chemotherapeutic drugs (thermochemotherapy) for intraperitoneal tumors. This observed enhancement may be due in part to increased tumor cell membrane permeability and greater drug metabolism by the cells. Hyperthermia may also provide a means to increase regional circulatory dilation and perfusion, which has implications for more effectively perfusing tumor tissue with CED. No studies have investigated the effect of CED perfusion of MGs with laser-induced local hyperthermia.
What is needed, and what embodiments of the present invention provide is a significantly more effective treatment for MGs in which a chemotherapeutic drug is more uniformly and broadly delivered to primary tumor and infiltrative cells (extending >2 cm) thereby diminishing the likelihood of tumor recurrence by allowing simultaneous and co-localized delivery of light and chemotherapy to targeted tissue.
Further, for example, the treatment of urinary bladder cancer is yet another specific type of cancer that may benefit from embodiments of the present invention. Urinary bladder cancer is the fourth most common non-cutaneous malignancy of humans in the United States with approximately 71,000 new cases diagnosed and 15,000 deaths in 2010. UCC, synonymous with transitional cell carcinoma, accounts for approximately 90% of all bladder cancers. Over 30% of UCCs are at an advanced clinical stage when diagnosed, with penetration of tumor cells into the muscularis propia (stages 3 and 4), serosa (stage 4 only), and metastasis to surrounding organs. Radical cystectomy of invasive UCC is the current standard treatment, but its use frequently results in significant post-operative complications. This radical treatment typically requires removal of the bladder, nearby lymph nodes, and part of the urethra in both sexes; the prostate, seminal vesicles, and vas deferens in men; and the ovaries, fallopian tubes, and part of the vagina in women, leading to poor patient quality of life.
Although patient outcomes for advanced stage, invasive bladder cancers are statistically poor, patient outcomes for early stage (stages 0-1) bladder cancers are relatively hopeful. The primary treatment for such early lesions is transurethral resection of the bladder (TURB) followed by chemotherapy. One of the original laser-based alternatives for treatment of superficial bladder tumors was Nd:YAG laser photocoagulation at a 1064 nm wavelength. Unfortunately, laser energy delivered at this wavelength can be damaging to underlying tissues. See Syed, H. A., et al., “Holmium:YAG laser treatment of recurrent superficial bladder carcinoma: Initial clinical experience.” Journal of Endourology, 2001. 15(6): p. 625-627, the disclosure of which is incorporated by reference herein in its entirety. Nd:YAG-based treatments were succeeded by the Ho:YAG laser (2.1 μm wavelength) for photothermal treatment of superficial bladder cancers, which has become widely utilized. Several studies have shown that treatment with the Ho:YAG laser is safe, effective, and associated with rapid patient recovery, indicating it is a viable alternative to standard TURB or electrocautery for treating early stage bladder cancer. While effective for superficial tumors, Ho:YAG laser treatment has proven ineffective for invasive, late stage bladder tumors due to insufficient light penetration into the tumor mass. See Johnson, D. E., “Use of the Holmium-Yag (Ho Yag) Laser for Treatment of Superficial Bladder-Carcinoma.” Lasers in Surgery and Medicine, 1994, 14(3): p. 213-218, the disclosure of which is incorporated by reference herein in its entirety. Light at a wavelength of 2.1 μm penetrates bladder tissue approximately 0.5 mm, which is insufficient to treat late-stage tumors that invade the muscular and serosal layers 2-4 mm into the bladder wall. See Hruby, G. W., et al., “Transurethral bladder cryoablation in the porcine model.” Journal of Urology, 2008. 179(4), the disclosure of which is incorporated by reference herein in its entirety. Inadequate delivery and heating of deep tumor volumes result in generation of poorly defined lesion boundaries and a high likelihood of tumor re-growth, recurrence, necrosis, and possible perforation of the bladder wall.
What is needed, and what embodiments of the present invention provide methods using FMD devices that are capable of penetrating the bladder mucosa and muscularis to co-deliver exogenous photoabsorbers and light interstitially, thereby increasing the spatial control of treatment.
Even further, on the cosmetic surgery front, improvements in treatment protocols especially for fat re-shaping procedures and the like are also needed. More particularly, in such treatment protocols, focused or near-collimated light only travels a few millimeters into turbid tissues, due to the combined effects of photon scattering and absorption. Many laser cosmetic procedures, such as laser lipolysis and hair removal, have limited efficacy and restricted uses, due to the short penetration depth of ht into skin and underlying tissue. Other potential applications, such as treatment/ablation of skin tumors, are similarly limited by this obstacle. Therefore, light-guiding optical fibers with flat end faces are commonly used to deliver visible and near-infrared light interstitially to deeper tissue regions, However, an optical fiber with a flat end face limits the laser power that can be delivered safely because high irradiance at the tip leads to excessive temperature elevation, causing both carbonization of the tissue and thermal damage to the fiber itself.
To deliver increased amounts of therapeutically useful energy to large tissue regions, several types of optical diffusers have been developed. Such optical diffusers provided uniform delivery of light from their surfaces for photothermal and photochemical laser therapy procedures. Even though the radiant emittance profile can be well-controlled at the surface of the diffuser, the fluence distribution inside the tissue is determined by inherent tissue optical properties, limiting the volume of tissue that can be treated with a single diffuser. Multiple diffusers have been shown to deliver effective levels of laser energy to larger tissue volumes.
Thus, what is needed and what the inventors provide, is a new microneedle design that delivers light circumferentially along a length of 3 mm, functioning as a microscale optical diffuser for laser therapy procedures.